Study on the Antitumor Mechanism of Tanshinone IIA In Vivo and In Vitro through the Regulation of PERK-ATF4-HSPA5 Pathway-Mediated Ferroptosis.

As a traditional Chinese medicine, Salvia miltiorrhiza Bunge was first recorded in the Shennong Materia Medica Classic and is widely used to treat "the accumulation of symptoms and masses". The main active ingredient of Salvia miltiorrhiza Bunge, Tanshinone IIA (TIIA), has shown anti-inflammatory, antitumor, antifibrosis, antibacterial, and antioxidative activities, etc. In this study, the results showed that TIIA could inhibit the proliferation and migration of HepG2 cells and downregulate glutathione (GSH) and Glutathione Peroxidase 4 (GPX4) levels; besides, TIIA induced the production of Reactive Oxygen Species (ROS), and upregulated the total iron content. Based on network pharmacology analysis, the antitumor effect of TIIA was found to be focused on the endoplasmic reticulum (ER)-mediated ferroptosis signaling pathway, with protein kinase R (PKR)-like ER kinase (PERK)-activating transcription factor 4 (ATF4)-heat shock 70 kDa protein 5 (HSPA5) as the main pathway. Herein, TIIA showed typical ferroptosis characteristics, and a ferroptosis inhibitor (ferrostatin-1) was used to verify the effect. The antitumor effects of TIIA, occurring through the inhibition of the PERK-ATF4-HSPA5 pathway, were further observed in vivo as significantly inhibited tumor growth and the improved pathological morphology of tumor tissue in H22-bearing mice. In summary, the antitumor mechanism of TIIA might be related to the downregulation of the activation of PERK-ATF4-HSPA5 pathway-mediated ferroptosis.

Government and dealer regulatory decisions on producer illegal production in China's food supply chain.

Illegal food production in China has proliferated in recent years, triggering serious public concerns on food safety. In this work, we model a regulatory event in a food supply chain comprising a local government, a dealer, and a producer involved in illegal food production, and get equilibrium regulatory decisions of the government and the dealer, and equilibrium production decisions of the producer. The results show that: 1) in a situation where the producer is likely to produce illegally, the government does not regulate, and implements insufficient or sufficient regulation according to the utility-cost ratio of regulating. 2) The regulatory decisions of the dealer depend not only on the regulatory decisions of the government but also on the utility-cost ratio of regulating. 3) Only when the joint regulatory intensity of the government and the dealer is not less than a certain threshold value, the producer will not produce illegally, and the threshold value is the optimal regulatory intensity jointly implemented by the government and the dealer. Otherwise it is ineffective, inadequate, or excessive regulation. Therefore, we suggest that the government and the dealer jointly make regulatory decisions to achieve optimal regulation at the lowest regulatory cost and evade illegal food production by the producer.

A dual-channel secondary closed-loop supply chain considering retail groups and fairness concerns.

The rise of retail groups has strengthened their voice in the supply chain, drawing more attention from supply chain members to the issue of profit fairness. To explore the influence of fairness concerns on operational decisions in closed-loop supply chains after the formation of retail groups. In this paper, we first construct a secondary dual-channel closed-loop supply chain led by a retail group and followed by a manufacturer. Next, the corresponding game models are constructed under three scenarios, namely, fairness neutrality (FN), fairness concerns of the retail groups (FR), and fairness concerns of the manufacturer (FM), respectively. Finally, the game models are solved and analyzed. It turns out that it is easier for the manufacturer to satisfy its demands for fairness by adjusting the wholesale price. Furthermore, we find that fairness concerns do not enhance the recycling rate of used products and the greenness of remanufacturing. For retail groups, fairness concerns can hurt their profits, but appropriate fairness concerns can contribute to profitable growth in their retail business. Interestingly, the manufacturer's fairness concerns do not affect the total profitability of the supply chain system, but the retail group's fairness concerns do. This paper identifies dual changes in the scope of operations and power structure of retail groups in closed-loop supply chains, as well as analyzes the fairness concerns raised by these changes, which will lead to new recommendations for operational decision-making in firms.

Cooling Subgrade Effectiveness by L-Shaped Two-Phase Closed Thermosyphons with Different Inclination Angles and XPS Insulation Boards in Permafrost Regions.

This study focused on the coupling heat transfer mechanism and the cooling efficiency of L-shaped two-phase closed thermosyphons (L-shaped TPCTs) in the wide subgrade of permafrost regions. Considering the fact that time-space dynamics change the effects of the air temperature, wind speed, and geotemperature, a coupled air temperature-L-shaped TPCT-subgrade soil heat transfer model was established using the ANSYS 15.0 software platform, and the rationality of the model was verified through measured data. The heat-transfer characteristics of the L-shaped TPCTs and the long-term thermal stability of the subgrade were studied under different inclination angles of the evaporator (α = 15°, 30°, 50°, 70°, and 90°). Then, the cooling effectiveness of a composite subgrade with TPCTs and an XPS insulation board was numerically calculated. The results show that the heat flux of the L-shaped TPCT was the greatest when α = 50°, and the heat flux reached the maximum value of 165.7 W·m-2 in January. The L-shaped TPCT had a relatively good cooling effect on the subgrade as a whole when α = 50° and 70°, but the thawing depth at the center of the subgrade with L-shaped TPCTs reached 9.0 m below the ground surface in the 30th year. The composite subgrade with L-shaped TPCTs/vertical TPCT/XPS insulation board is an effective method to protect the permafrost foundation and improve the long-term thermal stability of the wide subgrade. The maximum heat flux of evaporation section of the L-shaped TPCT is 18.8% higher than that of the vertical TPCT during the working period of the TPCTs of the composite subgrade.

Transmitted Drug Resistance in Antiretroviral Therapy-Naive Persons With Acute/Early/Primary HIV Infection: A Systematic Review and Meta-Analysis.

Background: The widespread use of antiretroviral therapy (ART) has raised concerns about the emergence of HIV transmitted drug resistance (TDR). Acute HIV infection (AHI) was the most appropriate time to detect the spread of TDR. In this meta-analysis, our purpose was to evaluate the level of TDR in ART-naive patients with primary HIV infection (PHI)/AHI/early HIV infection (EHI) and to describe the critical drug-resistant mutations. Methods: We systematically searched the literature between January 1, 2008, and April 30, 2021, in PubMed, Web of Science, Embase, and the Cochrane Library. To evaluate the overall prevalence of TDR, we extracted raw data and analyzed prevalence estimates using Stata SE. Results: The data of this meta-analysis come from 12 observational studies, covering 3,558 ART-naive individuals with PHI, AHI, or EHI. The overall prevalence of HIV-TDR is 9.3% (95% CI: 6.8%-11.8%, I2 = 81.1%, in 11 studies). The prevalence of resistance by drug class is the highest for the nonnucleoside reverse transcriptase inhibitors (NNRTIs) at 5.7% (95% CI: 2.9%-8.5%, I2 = 96.6%, in 11 studies), followed by nucleoside reverse transcriptase inhibitors (NRTIs) at 3.4% (95% CI: 1.8%-5.0%, I2 = 86.3%, in 10 studies) and protease inhibitors (PIs) at 3.3% (95% CI: 2.7%-3.9%, I2 = 15.6%, in 10 studies). The prevalence of TDR to integrase inhibitors (INIs) is 0.3% (95% CI: 0.1%-0.7%, I2 = 95.9%, in three studies), which is the lowest among all antiretroviral drugs. Conclusion: The overall prevalence of TDR is at a moderate level among AHI patients who have never received ART. This emphasizes the importance of baseline drug resistance testing for public health surveillance and guiding the choice of ART. In addition, the prevalence of TDR to NNRTIs is the highest, while the TDR to INIs is the lowest. This may guide the selection of clinical antiretroviral drugs.

Three-Drug Regimens Containing Integrase Inhibitor Show Good Efficacy and Safety in Treatment-Naive Patients With HIV-1: A Bayesian Analysis.

Introduction: The extensive utilisation of antiretroviral therapy has greatly improved the survival rates of those infected with human immunodeficiency virus (HIV). The objective of this study was to compare 3-drug regimens containing non-nucleoside reverse transcriptase inhibitor with 3-drug regimens containing integrase inhibitor (INI) regarding efficacy and safety in treatment-naive HIV-1-infected adults at 48 and 96 weeks, respectively. Methods: This study was a network meta-analysis using a Bayesian methodology. On January 8, 2020, we searched databases and other sources for randomized controlled trials conducted in treatment-naive HIV-1 adults and compared multiple 3-drug antiretroviral regimens containing INI, efavirenz (EFV), or rilpivirine (RPV). We extracted data on the following outcomes: virologic suppression, CD4+ cell recovery, discontinuations, deaths, adverse events, serious adverse events, deaths related to study drugs, and drug-related adverse events. We conducted calculations within a Bayesian framework using R software. Results: The network contained 15 randomized controlled trials including 9,745 patients. For efficacy outcomes, regimens containing INI, especially dolutegravir (DTG), were generally superior to other regimens. For virologic suppression at 48 weeks, odds ratios (95% credible intervals) were 0.6 (0.43, 0.82) for EFV+ tenofovir disoproxil fumarate (TDF)+emtricitabine (FTC) versus DTG+ abacavir+ lamivudine (3TC) and 0.52 (0.36, 0.75) for EFV+TDF+FTC vs. DTG+TDF+FTC/3TC. For safety outcomes, regimens containing INI tended to be safer relative to regimens without INI. Outcomes associated with death were unsuitable for network meta-analysis due to low event rates. Conclusion: 3-drug regimens containing INI demonstrate better efficacy and safety than those containing RPV or EFV.

Bifunctional Fluorophosphonium Triflates as Intramolecular Frustrated Lewis Pairs: Reversible CO2 Sequestration and Binding of Carbonyls, Nitriles and Acetylenes.

Electrophilic fluorophosphonium triflates bearing pyridyl (3[OTf]) or imidazolyl (4[OTf])-substituents act as intramolecular frustrated Lewis pairs (FLPs) and reversibly form 1 : 1 adducts with CO2 (5+ and 6+ ). An unusual and labile spirocyclic tetrahedral intermediate (72+ ) is observed in CO2 -pressurized (0.5-2.0 bar) solutions of cation 4+ at low temperatures, as demonstrated by variable-temperature NMR studies, which were confirmed crystallographically. In addition, cations 3+ and 4+ actively bind carbonyls, nitriles and acetylenes by 1,3-dipolar cycloaddition, as shown by selected examples.

Design of Incentive Contract for Technological Innovation of New Energy Vehicles with Asymmetric Information.

The improvement of China's new energy automobile technology is one of the most pressing issues for the government and manufacturers, given that the existing new energy automobile subsidy policy is about to be withdrawn completely. Considering that the manufacturer has the private information of the initial technology level of new energy vehicles, its technology can be improved by means of technological innovation. Using principal-agent and regulation theory, this paper studies how the government designs incentive contracts to motivate manufacturers to strive to upgrade new energy automotive technology. The study has obtained a quantitative incentive contract under full information and a quantitative screening contract with asymmetric information, which provides an effective reference for the design of government subsidy contracts. It was found that the existence of asymmetric information reduces the expected net utility of the government in incentive projects, and the technology upgrading of low-level manufacturers is insufficient, but will not affect the technology upgrading of high-level manufacturers who will get information rent. The conclusion has good reference value and guiding significance for government policy-making with asymmetric information.

Pricing Strategy of Construction and Demolition Waste Considering Retailer Fairness Concerns under a Governmental Regulation Environment.

In order to investigate the issues of the recycling and remanufacturing of construction and demolition waste (C&D waste), this paper develops a closed-loop supply chain (CLSC) consisting of a manufacturer, a retailer, and a recycler, considering both the retailer's fairness concern psychology and governmental regulations. Four mathematical models are developed for the calculations, and the models are solved through game theory. In both the decentralized and centralized scenarios, the members' strategies are discussed and the optimal values of decision variables are determined. A numerical study is carried out for sensitivity analyses to verify the accuracy of the theoretical conclusions. The results reveal that retailer fairness concerns lead to a decrease in the wholesale price of building materials and negatively affect manufacturers' profits. Additionally, governmental regulations can effectively increase the recycling amount and improve the utilization rate of C&D waste, and promote a virtuous cycle of the recycling and remanufacturing of C&D waste.

Analysis of the Evolution Game of Construction and Demolition Waste Recycling Behavior Based on Prospect Theory under Environmental Regulation.

With the development of the construction industry, increasing concern over construction and demolition waste (CDW) has initiated a wave of environmental regulation by the government in order to reduce the environmental impact and ensure sustainable development. Research on behavioral decision-making can offer a theoretical basis for the government and individuals. This paper aims to study the behavioral decision-making of stakeholders in CDW recycling under environmental regulation. Considering the limited rationality of stakeholders and the difference in reference points, an evolutionary game model including contractors and manufacturers of construction materials is proposed based on the prospect theory of behavioral economics. The results indicate that, only when the perceived benefits of one or both stakeholders for participation under the environmental regulation exceed those for non-participation, can the CDW recycling system eventually evolve to a stable state in which both stakeholders choose to participate. In addition, factors such as the initial strategy, production cost, technology, subsidies, recycling benefits, and the degree of perception of the stakeholders, exert certain influences on the stable state. To attain the required stable state, the government should increase the subsidies for the stakeholders and strengthen the publicity regarding recycling effects to improve the perceived benefits.

Acute kidney injury in China: a cross-sectional survey.

BACKGROUND: Acute kidney injury (AKI) has become a worldwide public health problem, but little information is available about the disease burden in China. We aimed to evaluate the burden of AKI and assess the availability of diagnosis and treatment in China. METHODS: We launched a nationwide, cross-sectional survey of adult patients who were admitted to hospital in 2013 in academic or local hospitals from 22 provinces in mainland China. Patients with suspected AKI were screened out on the basis of changes in serum creatinine by the Laboratory Information System, and we reviewed medical records for 2 months (January and July) to confirm diagnoses. We assessed rates of AKI according to two identification criteria: the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) AKI definition and an increase or decrease in serum creatinine by 50% during hospital stay (expanded criteria). We estimated national rates with data from the 2013 report by the Chinese National Health and Family Planning Commission and National Bureau of Statistics. FINDINGS: Of 2,223,230 patients admitted to the 44 hospitals screened in 2013, 154,950 (7·0%) were suspected of having AKI by electronic screening, of whom 26,086 patients (from 374,286 total admissions) were reviewed with medical records to confirm the diagnosis of AKI. The detection rate of AKI was 0·99% (3687 of 374,286) by KDIGO criteria and 2·03% (7604 of 374,286) by expanded criteria, from which we estimate that 1·4-2·9 million people with AKI were admitted to hospital in China in 2013. The non-recognition rate of AKI was 74·2% (5608 of 7555 with available data). Renal referral was done in 21·4% (1625 of 7604) of the AKI cases, and renal replacement therapy was done in 59·3% (531 of 896) of those who had the indications. Delayed AKI recognition was an independent risk factor for in-hospital mortality, and renal referral was an independent protective factor for AKI under-recognition and mortality INTERPRETATION: AKI has become a huge medical burden in China, with substantial underdiagnosis and undertreatment. Nephrologists should take the responsibility for leading the battle against AKI. FUNDING: National 985 Project of China, National Natural Science Foundation of China, Beijing Training Program for Talents, International Society of Nephrology Research Committee, and Bethune Fund Management Committee.